Relevance of S S1/S2 “priming” by host proteases for viral fusion to cells. The left cells produce viruses that can be “primed” by endogenous proteases such as furin (blue scissors); other viruses are not primed when they exit the cell. The primed viruses (marked by a yellow internal shadow) reach another cell (pathway A), where a membrane protease (e.g., TMPRSS2) may cleave the S2’ site (see Figure RB1b) leading to membrane fusion and delivery of viral RNA. Non-primed viruses can deliver their genome by two routes: in B, the virus reaches the cell, is primed on the membrane at both S1/S2 and S2’ by a local protease and then fuse with the plasma membrane; alternatively, in C the virus is internalized by endocytosis and priming/fusion occurs in endocytic vesicles. Note that also “primed” viruses may undergo pathway C, depending on their interaction with the recipient cell.